{"data":{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:41612311", "kind": "science-record", "revision": 3, "content_hash": "sha256:b9087c78446631af999afa00cc3c819fa8e53caf2ad363b7fbe7d90ff4a47e1d", "created_at": "2026-11-01T20:31:42Z", "updated_at": "2026-11-01T22:15:31Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Integrated single-cell and bulk RNA sequencing unravels neutrophil heterogeneity and validates SPP1 as a prognostic biomarker in cervical cancer.", "doi": "10.1186/s12885-026-15636-9", "pmid": "41612311", "authors": ["Siting Lin", "Junlin Zhong", "Shengjin Yuan", "Manting Su", "Yiwang Zhang", "Xinling Zhang"], "journal": "BMC cancer", "year": 2026, "abstract": "BACKGROUND: Cervical cancer (CC) remains a major global health burden, with tumor microenvironment (TME) plasticity and immune evasion driving its progression. The intricate heterogeneity of neutrophils and their complex crosstalk within the TME remain poorly understood, thereby limiting the development of targeted therapeutic strategies. Single-cell RNA sequencing (scRNA-seq) provides an unprecedented level of resolution for dissecting neutrophil subpopulations and elucidating their roles in CC pathogenesis.\nMETHODS: We integrated scRNA-seq data from CC tissues (GSE208653, n = 5) with bulk RNA-seq cohorts from The Cancer Genome Atlas - Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA-CESC) and Genotype-Tissue Expression (GTEx) database. Using Seurat-based clustering, pseudotime trajectory analysis and CellChat, we mapped neutrophil dynamics and intercellular communication networks. Differentially expressed genes (DEGs) were analyzed using the limma package, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses. A prognostic model was subsequently constructed via LASSO-Cox regression. Key targets were further validated through both in vitro functional assays, immunohistochemical (IHC) and immunofluorescence (IF) analyses of human pathological specimens.\nRESULTS: Four functionally distinct neutrophil subtypes, including immature, mature, antitumor, and interferon-stimulated populations, were characterized in CC, demonstrating dynamic heterogeneity during tumorigenesis. Secreted Phosphoprotein 1 (SPP1) was identified as a critical differentially expressed gene, with the SPP1-CD44 axis serving as a key mediator of neutrophil-tumor cell crosstalk. Downregulation of SPP1 markedly suppressed CC cell migration, invasion, and proliferation. Furthermore, a prognostic signature based on risk stratification efficiently categorized patients into high- and low-risk cohorts, with validated clinical utility in predicting survival outcomes.\nCONCLUSIONS: Our study comprehensively characterized the TME in CC through single-cell transcriptomics. Integrated analysis with bulk RNA-seq established and validated a robust prognostic signature, identifying SPP1 as a key oncogenic driver. The SPP1-centric model demonstrates significant clinical utility for risk stratification. These findings provide new insights into neutrophil heterogeneity and establish a mechanistic foundation for precision therapeutics in CC.", "claims": [{"id": "claim-method", "statement": "A prognostic model was subsequently constructed via LASSO-Cox regression.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:41612311", "locator": "sections[0] \"Abstract\" paragraph 2", "quote": "A prognostic model was subsequently constructed via LASSO-Cox regression."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The cervical cancer (CC) scRNA-seq dataset file of GSE208653 was downloaded from the Gene Expression Omnibus (GEO) database ( [https://www.ncbi.nlm.nih.gov/geo/] ). The bulk RNA-seq cohorts were obtained from the TCGA database ([https://portal.gdc.cancer.gov/] ) and the Genotype-Tissue Expression (GTEx) database ( [http://gtexportal.org/home/] ). All data supporting the conclusions are available from the authors on reasonable request.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:41612311", "locator": "sections[31] \"Data availability\" paragraph 2", "quote": "The cervical cancer (CC) scRNA-seq dataset file of GSE208653 was downloaded from the Gene Expression Omnibus (GEO) database ( [https://www.ncbi.nlm.nih.gov/geo/] ). The bulk RNA-seq cohorts were obtained from the TCGA database ([https://portal.gdc.cancer.gov/] ) and the Genotype-Tissue Expression (GTEx) database ( [http://gtexportal.org/home/] ). All data supporting the conclusions are available from the authors on reasonable request."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Furthermore, a prognostic signature based on risk stratification efficiently categorized patients into high- and low-risk cohorts, with validated clinical utility in predicting survival outcomes.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:41612311", "locator": "sections[21] \"Prediction and validation of prognostic gene signatures\" paragraph 2", "quote": "Time-dependent ROC curve analysis validated the signature’s predictive efficacy for overall survival, with training cohort AUCs of 0.62 (3-year), 0.62 (4-year) and 0.66 (5-year), and internal validation cohort AUCs of 0.64 (3-year), 0.73 (4-year) and 0.68 (5-year) (Fig. 6J-K)."}, {"asset": "source:pmid:41612311", "locator": "sections[21] \"Prediction and validation of prognostic gene signatures\" paragraph 2", "quote": "The AUCs for 3-, 4-, and 5-year survival in the external validation cohort were 0.71, 0.68, and 0.63, respectively (Fig. 6L)."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "Furthermore, a prognostic signature based on risk stratification efficiently categorized patients into high- and low-risk cohorts, with validated clinical utility in predicting survival outcomes.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:41612311"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE208653"], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "complete", "blocked_on": null, "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE208653"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:41612311", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1186/s12885-026-15636-9", "sha256": "sha256:607496b3f735ed4af3551e7805e3663d01659d2696cc88a7202aee1ea9430174", "bytes": 61239, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.1186/s12885-026-15636-9", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC12930679", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE208653", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE208653", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE208653", "version": null, "note": "The cervical cancer (CC) scRNA-seq dataset file of GSE208653 was downloaded from the Gene Expression Omnibus (GEO) database ( [https://www.ncbi.nlm.nih.gov/geo/] ). 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Integrated analysis with bulk RNA-seq established and validated a robust prognosti", "targeted therapeutic strategies. Single-cell RNA sequencing (scRNA-seq) provides an unprecedented level", "from CC tissues (GSE208653, n = 5) with bulk RNA-seq cohorts from The Cancer Genome Atlas - Cervi"], "order_basis": "paper_text_order:0", "id": "assay:1"}, {"role": "data_generation", "definition_id": "scrna_seq", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "unsupported", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["elopment of targeted therapeutic strategies. Single-cell RNA sequencing (scRNA-seq) provides an unprecedented level", "ensively characterized the TME in CC through single-cell transcriptomics. Integrated analysis with bulk RNA-seq estab", "utic strategies. Single-cell RNA sequencing (scRNA-seq) provides an unprecedented level of resoluti", "s in CC pathogenesis. METHODS: We integrated scRNA-seq data from CC tissues (GSE208653, n = 5) with"], "order_basis": "paper_text_order:442", "id": "assay:2"}, {"role": "data_generation", "definition_id": "ihc", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["ted through both in vitro functional assays, immunohistochemical (IHC) and immunofluorescence (IF) analyses o", "tional assays, immunohistochemical (IHC) and immunofluorescence (IF) analyses of human pathological specimen", "itro functional assays, immunohistochemical (IHC) and immunofluorescence (IF) analyses of hum", "on of Helsinki. Hematoxylin and eosin (H&E), immunohistochemistry (IHC) and immunofluorescence (IF) analyses w"], "order_basis": "paper_text_order:1349", "id": "assay:3"}, {"role": "data_generation", "definition_id": "clinical_cohort", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.85, "evidence": ["lyses were performed in tumor tissues from 6 patients with CC. The tissue samples were collected after"], "order_basis": "paper_text_order:2991", "id": "assay:4"}, {"role": "data_generation", "definition_id": "transfection", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["embedded in paraffin. Cell culture and cell transfection Human SiHa cells were obtained from Procell", "of the cell line reached 50–60%, cells were transfected with 50 pmol/mL small interfering RNA (siRNA", "/mL small interfering RNA (siRNA) using RNAi transfection reagent (D-Nano Therapeutics, Beijing, China", "ected with 50 pmol/mL small interfering RNA (siRNA) using RNAi transfection reagent (D-Nano The"], "order_basis": "paper_text_order:3195", "id": "assay:5"}, {"role": "data_generation", "definition_id": "cell_culture", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.77, "evidence": ["m Procell Company (Wuhan, China). Cells were cultured in Minimum Essential Medium (MEM, Procell) supp"], "order_basis": "paper_text_order:3286", "id": "assay:6"}, {"role": "analysis", "definition_id": "survival_analysis", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["cox_ph"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["A prognostic model was subsequently constructed via LASSO-Cox regression."], "order_basis": "consumes_earlier_output", "id": "assay:7"}]},"meta":{"api_version":"v1","automation_ladder_snapshot":"ba34b49490d9bfaf","automation_ladder_caveats":["Method extraction is rule-based and has no hand-judged accuracy sample. Evidence bands order textual support; method agreement intervals are null (n=0), never probabilities. Work-type validation does not validate methods.","Operation coverage describes only explicitly named methods. It does not prove a complete protocol, compatible parameters, successful compilation or re-execution. Unrecognised or ambiguous methods require review.","Data reachability is a textual accession or public-data statement. No dataset was downloaded or checked for access, completeness or licence.","Capabilities are planning states seeded from the dated equipment register. No bench ownership, completed quote or partner booking is inferred. Procurement counts are dependencies, not guaranteed replications or financial returns.","Tier and blocker counts are deterministic assessments of this corpus, not measured agreement. R3 is reserved for procurement; unresolved methods and data require human work (R4). The most restrictive axis wins, with capability, method, data as tie-breaks. Resolving one blocker can leave another at the same tier."],"engine":"corpus_engine","engine_provider":"rule_based_v1+lex99e1195c7d6f","run_id":"run-20261023T122449232913","source":"esearch","source_detail":"PubMed mirror biomed_pubmed (read-only)","run_status":"complete","imported_at":"2026-11-03T20:16:52+00:00","generated_at":"2026-11-04T00:40:44+00:00","total_papers":5529,"total_assays_tracked":29,"automatable_assay_families":6,"validated":true,"caveat_count":9,"blocking_caveats":5,"caveats":[{"code":"low_evidence_dominates","basis":["4,152 of 5,529 classifications (75.1%) matched no cue evidence and sit at the 0.05 floor.","34 of 230 data_only calls (14.8%) are in that group."],"claim":"Work type and confidence bands","gloss":"Most records were classified from their title and framing alone, with assay-cue coverage at zero.","detail":"Most classifications in this run rest on no matched evidence at all. At the evidence floor the work type comes from title framing and a fixed prior, not from anything in the paper, so the published work-type split should be read as a rough triage signal rather than a measured distribution. The impact is bounded but not removed: since 2026-10-23 the engine excludes floor-confidence records from the shortlist entirely and publishes them separately as held out, so the recommendation is unaffected even though the census is.","status":"unverified","severity":"high"},{"code":"runtime_is_modelled","basis":["Runtime is summed from published per-assay hour figures. Timing awaits the first executed replication.","4,407 of 5,529 records (79.7%) model to 0.00 hours because no assay was matched, which the ranking then reads as \"cheapest\".","0 of 10 shortlisted records carry a 0.00-hour estimate."],"claim":"Estimated replication runtime","gloss":"The hour figures are estimates built from assay mentions; timing awaits the first executed replication.","detail":"The hour figures are a cost model derived from the bench steps implied by each matched assay family. The first executed replication will supply measured timing. Records without an assay match currently receive a zero-hour model value.","status":"unverified","severity":"high"},{"code":"signal_score_without_citations","basis":["5,529 of 5,529 records (100.0%) have no citation count from the source metadata."],"claim":"Signal score","gloss":"The signal score uses publication-type weight because the mirror supplied zero citation counts.","detail":"The source supplied no citation counts for any record in this run, so the signal score is publication-type weight only. The citation term of the ranking is inert here, and the shortlist is ordered by publication type alone.","status":"unverified","severity":"high"},{"code":"abstract_absent","basis":["1,667 of 5,529 records (30.2%) carry no abstract at all."],"claim":"Evidence base for classification","gloss":"Some records contain a title and publication type only, defining the available classification evidence.","detail":"Where the mirror contains a title and publication types only, those fields define the classifier evidence. A methods section is required for fuller automated and human review.","status":"unverified","severity":"medium"},{"code":"classifier_agreement_measured","basis":["Published two-way decision agreement 77.7% (310 of 399 decidable records) from a stratified hand-check of 438 real records.","Three-way diagnostic agreement 73.9% (288 of 390 decidable records).","data_only agreement 75.2% (100 of 133 decidable).","48 record(s) could not be decided from title and abstract and were excluded from the denominator.","56 analysis-only records were published under another work type, so the data_only share is not an upper bound."],"claim":"Published automatable decision","gloss":"This figure has been checked against a human reading the same papers, so we know how often it is right.","detail":"The published automatable / not-automatable distribution comes from a rule-based classifier that was hand-checked against a fixed ground-truth definition. The agreement rates below are measured, not estimated. The three-way work type remains a diagnostic and is reported separately.","status":"measured","severity":"high"},{"code":"llm_comparison_not_measured","basis":["rule_based_v1+lex99e1195c7d6f produced 5,529 of 5,529 classifications.","Measured on 438 labelled records; these are RULE-BASED figures, not model results."],"claim":"Rule-based versus LLM agreement","gloss":"Every number here is the rule engine’s own. Model comparison begins when a working API credential is connected and measured.","detail":"The published two-way decision agreed with a human reading on 310 of 399 decidable records (77.7%). The diagnostic three-way label agreed on 288 of 390 decidable records (73.9%). Every percentage in this run belongs to the rule engine. Model comparison begins when a working API credential is connected and measured.","status":"not_measured","severity":"high"},{"code":"confidence_is_a_band","basis":["low band: 135 of 210 hand-judged records were correct, 64.3% [57.6, 70.5] (95% CI).","medium band: 80 of 104 hand-judged records were correct, 76.9% [68.0, 84.0] (95% CI).","high band: 73 of 76 hand-judged records were correct, 96.0% [89.0, 98.7] (95% CI).","A fitted calibrated probability was built, measured and withdrawn: it overstated held-out accuracy and reorders nothing."],"claim":"Confidence band and evidence score","gloss":"The confidence band carries a measured accuracy interval; 0.85 represents relative rank strength.","detail":"Confidence on this run is a BAND plus its measured accuracy interval. The number stored alongside each record is a monotone evidence score that orders records; 0.85 represents relative rank strength. A fitted probability was withdrawn after it overstated held-out accuracy. Threshold on the band.","status":"measured","severity":"medium"},{"code":"three_way_split_is_diagnostic","basis":["The corpus is published at the two-way decision: automatable or not-automatable. The three-way split (data_only / physical / mixed) is published as a diagnostic with its measured reliability attached, not as a claim, because the rule engine's `mixed` call cannot be defended.","The engine called 22 record(s) mixed; 10 matched the human judgement (45.5%, 95% CI 26.9-65.3).","The engine's `mixed` call is right on 10/22 hand-judged records (45.5%, 95% CI 26.9%-65.3%); a constant `physical` guess scores 36.4%.","The engine's `mixed` call does not reliably beat a constant `physical` guess on the hand-judged records it labels mixed.","The sign of that difference flips between two independent samples, so the three-way refinement is not demonstrably informative.","The mixed stratum contributes a disproportionate share of errors relative to its size.","At title-only depth the physical/mixed split collapses: a title says that work was done, not whether it was also analysed."],"claim":"The published decision is two-way","gloss":"The three-way split is shown for diagnosis only. The published split is two ways.","detail":"Count and filter the corpus on automatable versus not-automatable. The data_only / physical / mixed split remains an internal engine diagnostic because the mixed call has lower measured reliability.","status":"measured","severity":"medium"},{"code":"automatable_flag_unproven","basis":["6 of 29 assay families are marked automatable now: meta_analysis, machine_learning, survival_analysis, pca, molecular_docking, differential_expression.","The flag is a rule over assay family and work type; validation begins with the first executed replication.","It inherits the 75.2% data_only agreement rate, because the flag requires the record to be analysis-only."],"claim":"Automatable now","gloss":"This flag marks assay families the rules classify as data-only. The first executed replication will validate it.","detail":"This flag marks families the rules consider replicable from data alone. Its validity depends on the analysis-only classification and will be measured through an executed replication.","status":"unverified","severity":"medium"}],"confidence_policy":"band_with_measured_interval","confidence_contract":{"policy":"band_with_measured_interval","summary":"Confidence is reported as a BAND with a measured accuracy interval. The raw evidence score supplies monotone ordering. A fitted point estimate was withdrawn after it overstated held-out accuracy.","evidence_score":"A monotone evidence score in [0,1] built from cue mass, axis separation and text coverage. Use it to order records. Interpret 0.85 as relative rank strength.","confidence_band":"low | medium | high. Consumers threshold on this value.","band_accuracy":"Wilson 95% interval on the measured agreement of the hand-judged records in this band.","calibrated_confidence":"WITHDRAWN. Reintroduction requires held-out evidence demonstrating reliable estimates across every bin."},"band_accuracy":{"low":{"n":210,"low":0.576,"band":"low","high":0.7046,"agree":135,"accuracy":0.6429},"high":{"n":76,"low":0.8903,"band":"high","high":0.9865,"agree":73,"accuracy":0.9605},"medium":{"n":104,"low":0.6795,"band":"medium","high":0.8397,"agree":80,"accuracy":0.7692}},"provider":"rule_based_v1+lex99e1195c7d6f","lexicon_id":"99e1195c7d6f","contract_published_at":"2026-10-23T12:25:29.022232+00:00","confidence_is_band":true,"confidence_is_probability":false,"decision_taxonomy":"two_way","decidable_fraction_two_way":0.8854,"decidable_fraction_two_way_low":0.8565,"decidable_fraction_two_way_high":0.9143,"decidable_fraction_three_way":0.8586,"decidable_fraction_three_way_low":0.8287,"decidable_fraction_three_way_high":0.8884,"decidable_population":5529,"validation_sample_size":438,"three_way_cost_fraction":0.0268,"three_way_cost_records":148,"decision_counts":{"automatable":230,"not_automatable":5299},"decision_split":{"automatable":{"count":230,"share":0.04159884246699222},"not_automatable":{"count":5299,"share":0.9584011575330078}},"diagnostic_work_type_counts":{"mixed":24,"physical":5275,"data_only":230}}}